How the disulfide conformation determines the disulfide/thiol redox potential

Area of Science:

• Computational Chemistry
• Biochemistry
• Structural Biology

Background:

• Protein disulfide bonds exist in various conformations with differing energies.
• Experimental data suggest high-energy disulfides are more prone to reduction, but the mechanism is unclear.

Purpose of the Study:

• To computationally investigate the relationship between disulfide conformation and redox potential.
• To elucidate the structure-reactivity correlation of the disulfide bond.
• To understand the determinants of disulfide conformational energies and rotational barriers.

Main Methods:

• Utilized a computational approach with a diethyl disulfide model system.
• Employed quantitative molecular orbital theory to calculate redox potentials (E°).
• Decomposed E° into vertical electron affinity and reorganization terms.

Main Results:

• Relative conformational energy of diethyl disulfide correlates with its redox potential (E°).
• Identified key factors influencing disulfide conformational energies and rotational barriers.
• Findings are transferable to disulfide conformations found in the Protein Data Bank.

Conclusions:

• Strained, high-energy disulfide conformations exhibit a strong tendency for reduction.
• The enhanced reduction potential is primarily due to the release of unfavorable interactions upon reduction.
• Reorganization effects, rather than increased electron affinity, drive the high reduction potential of high-energy disulfides.